Monkeypox virus H3 protein (H3)

The Monkeypox virus H3 protein is a 324-amino-acid transmembrane protein conserved across orthopoxviruses, with its extracellular domain (residues 1-282) mediating viral adhesion to host cells via binding to cell-surface heparan sulfate (HS). This interaction, facilitated by a newly identified positively charged α-helical domain (residues ~240-282) rich in basic amino acids like R242, R248, R259, R267, and a Mg(II)-bound region, acts like a "thumb and palm" mechanism to guide and secure HS, enabling viral entry alongside fusion proteins. H3 exhibits a glycosyltransferase fold, binds UDP-glucose and HS, and serves as a major immune target, with neutralizing antibodies protecting against lethal poxvirus infections in animal models. Recent AI-driven studies using AlphaFold2, molecular dynamics, and experimental validation (AFM, flow cytometry, BLI) confirmed the helical domain's essential role, as mutating its charged residues reduces HS binding affinity and probability. Targeting this domain with designed inhibitors like AI-PoxBlock723 blocks H3-HS interaction and shows antiviral efficacy, highlighting H3's promise as a broad orthopoxvirus therapeutic target despite challenges in resolving dynamic HS structures.

Other names

H3L (Vaccinia virus ortholog)MPXV H3

Inhibition of HS binding by targeting the α-helical domain, blocking viral adhesion